The specific objective of our research is to establish the biochemical mechanisms involved in the degradation of DNA by certain antitumor drugs. Camptothecin, podophyllotoxin and bleomycin will be used to determine this mechanism in mammalian cells. The ability of these drugs to (a) bind to DNA, thus increasing its suceptibility to the action of endonucleases, (b) induce breaks in DNA by chemical interactions, and (c) inhibit normal repair synthesis in DNA will be studied. The chemical nature of single-strand breaks will be investigated. Structure-activity relationships in a series of camptothecin analogs will further elucidate the mechanisms involved in drug-induced fragmentation of DNA. BIBLIOGRAPHIC REFERENCES: L.L. Liao, S.M. Kupchan, and S.B. Horwitz. Mode of Action of the Antitumor Compound Bruceantin, an Inhibitor of Protein Synthesis. Molecular Pharmacology 12, 167-176 (1976). M. Takeshita, A.P. Grollman and S.B. Horwitz. Effect of ATP and Other Nucleotides on the Bleomycin-Induced Degradation of Vaccina Virus DNA. Virology 69, 453-463, (1976).